EP3448416B1 - Semaglutide in cardiovascular conditions - Google Patents

Semaglutide in cardiovascular conditions Download PDF

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Publication number
EP3448416B1
EP3448416B1 EP17721109.1A EP17721109A EP3448416B1 EP 3448416 B1 EP3448416 B1 EP 3448416B1 EP 17721109 A EP17721109 A EP 17721109A EP 3448416 B1 EP3448416 B1 EP 3448416B1
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Prior art keywords
semaglutide
pharmaceutical composition
use according
fatal
subject
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German (de)
English (en)
French (fr)
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EP3448416A1 (en
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Oluf Kristian Højbjerg HANSEN
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Novo Nordisk AS
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Novo Nordisk AS
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Priority to HRP20221150TT priority patent/HRP20221150T1/hr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the GLP-1 receptor agonist semaglutide for use in treating a subject having diabetes and high cardiovascular risk.
  • Diabetes is a metabolic disorder characterized by hyperglycaemia that is associated with a high risk of cardiovascular and other serious health-related consequences.
  • a person with diabetes is two to three times more likely to die from cardiovascular causes than people with no history of diabetes, even after controlling for other cardiovascular risk factors. They are also at very high risk of developing serious microvascular complications ultimately leading to premature death: nephropathy and renal failure, retinal disease and blindness, autonomic and peripheral neuropathy, as well as other conditions related to the cardiovascular system: hypertension, lower limb amputation, cognitive decline, and erectile dysfunction.
  • glycaemic control is the treatment goal in subjects with type 2 diabetes, since the risk of long-term complications is increased with poor glycaemic control.
  • a significant proportion of subjects with type 2 diabetes do not achieve the recommended target levels for glycaemic control and are at high risk of developing cardiovascular disease or microvascular complications.
  • there is an unmet medical need for treatment alternatives that not only provide glycaemic control but also reduce the risk of cardiovascular disease in subjects with type 2 diabetes.
  • the present invention relates to a pharmaceutical composition for use in a method for reducing the risk of a major adverse cardiovascular event (MACE) in subjects with type 2 diabetes mellitus and high cardiovascular risk, wherein said MACE is selected from the group consisting of
  • high cardiovascular risk refers to clinical evidence of at least one cardiovascular disease and/or subclinical evidence of at least one cardiovascular disease. In some embodiments high cardiovascular risk is present if the subject has clinical or subclinical evidence of at least one cardiovascular disease.
  • the present invention relates to use in a method of reducing the risk of MACE in subjects with type 2 diabetes mellitus and high cardiovascular risk. In some embodiments the present invention relates to use in a method of reducing the risk of MACE in subjects with type 2 diabetes mellitus and high cardiovascular risk, wherein said MACE is selected from the group consisting of non-fatal MI, non-fatal stroke, CV death caused by MI, and CV death caused by stroke. In some embodiments said MACE is selected from the group consisting of non-fatal MI and CV death caused by MI. In some embodiments said MACE is selected from the group consisting of non-fatal stroke and CV death caused by stroke.
  • Described herein is use in delaying myocardial infarction or stroke in subjects with type 2 diabetes mellitus and high cardiovascular risk.
  • the terms "delaying” as used herein refers to "preventing”.
  • Described herein is use in preventing cardiovascular events in subjects with type 2 diabetes, wherein said "cardiovascular events” is one or more major adverse cardiovascular events, and wherein “major adverse cardiovascular event” is as defined herein.
  • MACE is events selected from the group consisting of cardiovascular (CV) death, non-fatal MI, non-fatal stroke, revascularisation, hospitalisation for unstable angina pectoris, and hospitalisation for heart failure.
  • CV cardiovascular
  • non-fatal MI refers to non-fatal myocardial infarction.
  • MACE is events selected from the group consisting of CV death, non-fatal MI, and non-fatal stroke.
  • the use reduces or delays a major adverse cardiovascular event (MACE). In some embodiments the use reduces the risk of said subject developing a major adverse cardiovascular event (MACE). In some embodiments the use reduces the risk of said subject developing its first MACE.
  • MACE major adverse cardiovascular event
  • the MACE referred to herein is first MACE, e.g. after initiating administration of semaglutide.
  • first MACE refers to the first MACE event of a subject after initiation of semaglutide administration.
  • MACE is selected from the group consisting of CV death, non-fatal MI, non-fatal stroke, revascularisation, hospitalisation for heart failure, and hospitalisation for unstable angina pectoris.
  • MACE e.g. selected from the group consisting of CV death, non-fatal MI, non-fatal stroke, revascularisation, hospitalisation for heart failure, and hospitalisation for unstable angina pectoris
  • MACE is reduced or delayed by at least 1% compared to placebo.
  • MACE e.g. selected from the group consisting of CV death, non-fatal MI, non-fatal stroke, revascularisation, hospitalisation for heart failure, and hospitalisation for unstable angina pectoris
  • MACE e.g. selected from the group consisting of CV death, non-fatal MI, non-fatal stroke, revascularisation, hospitalisation for heart failure, and hospitalisation for unstable angina pectoris
  • MACE is reduced about 27% compared to placebo.
  • the first MACE e.g. selected from the group consisting of CV death, non-fatal MI, non-fatal stroke, revascularisation, hospitalisation for heart failure, and hospitalisation for unstable angina pectoris
  • the first MACE e.g.
  • the first MACE e.g. selected from the group consisting of CV death, non-fatal MI, non-fatal stroke, revascularisation, hospitalisation for heart failure, and hospitalisation for unstable angina pectoris
  • the first MACE is reduced about 27% compared to placebo.
  • MACE is selected from the group consisting of CV death, non-fatal MI, and non-fatal stroke. In some embodiments MACE (e.g. selected from the group consisting of CV death, non-fatal MI, and non-fatal stroke) is reduced or delayed by at least 10% compared to placebo. In some embodiments MACE (e.g. selected from the group consisting of CV death, non-fatal MI, and non-fatal stroke) is reduced or delayed by from about 20% to about 30% compared to placebo. In some embodiments MACE (e.g. selected from the group consisting of CV death, non-fatal MI, and non-fatal stroke) is reduced or delayed about 26% compared to placebo. In some embodiments MACE (e.g.
  • MACE e.g. selected from the group consisting of CV death, non-fatal MI, and non-fatal stroke
  • MACE has a hazard ratio of 0.74 with a 95% CI of (0.58; 0.95) compared to placebo.
  • the risk of said subject developing a MACE is reduced by at least 10% compared to placebo.
  • the subject developing its first MACE e.g.
  • the subject developing its first MACE e.g. selected from the group consisting of CV death, non-fatal MI, and non-fatal stroke
  • the subject developing its first MACE (e.g. selected from the group consisting of CV death, non-fatal MI, and non-fatal stroke) has a hazard ratio of 0.74 with a 95% CI of (0.58; 0.95) compared to placebo.
  • the MACE is non-fatal MI. In some embodiments the non-fatal MI is reduced or delayed by at least 10% compared to placebo. In some embodiments the non-fatal MI is reduced or delayed by from about 15% to about 35% compared to placebo. In some embodiments the non-fatal MI is reduced or delayed by about 26% compared to placebo.
  • the MACE is non-fatal stroke. In some embodiments the non-fatal stroke is reduced or delayed by at least 10% compared to placebo. In some embodiments the non-fatal stroke is reduced or delayed by from about 20% to about 60% compared to placebo. In some embodiments the non-fatal stroke is reduced or delayed by from about 30% to about 50% compared to placebo. In some embodiments the non-fatal stroke is reduced or delayed by about 39% compared to placebo.
  • the MACE is revascularisation. In some embodiments the revascularisation is reduced or delayed by at least 10% compared to placebo. In some embodiments the revascularisation is reduced or delayed by from about 20% to about 60% compared to placebo. In some embodiments the revascularisation is reduced or delayed by from about 30% to about 50% compared to placebo. In some embodiments the revascularisation is reduced or delayed by about 38% compared to placebo.
  • Revascularisation may be coronary revascularisation or peripheral revascularisation.
  • the MACE is hospitalisation for unstable angina pectoris. In some embodiments the hospitalisation for unstable angina pectoris is reduced or delayed by at least 10% compared to placebo. In some embodiments the hospitalisation for unstable angina pectoris is reduced or delayed by from about 10% to about 30% compared to placebo. In some embodiments the hospitalisation for unstable angina pectoris is reduced or delayed by about 18% compared to placebo.
  • the administration of semaglutide is a chronic treatment in which semaglutide is administered for at least 16 months (such as at least 30 months, and optionally up to 54 months), and wherein said use reduces or delays non-fatal myocardial infarction (MI).
  • MI myocardial infarction
  • the administration of semaglutide is a chronic treatment in which semaglutide is administered for at least 18 months (such as at least 30 months, and optionally up to 54 months), and wherein said use reduces the need or risk of requiring revascularisation.
  • the MACE is CV death. In some embodiments the CV death is reduced by at least 1% compared to placebo. In some embodiments the CV death is reduced or delayed by from about 1% to about 3% compared to placebo. In some embodiments the CV death is reduced or delayed by about 2% compared to placebo.
  • Placebo refers to a formulation identical to the semaglutide formulation except not comprising semaglutide and the placebo was administered in the volume used in the equivalent semaglutide dosage.
  • a subject receiving placebo may also include concomitant medication, such as one or more oral anti-diabetic drugs (OADs), or human NPH insulin or long-acting insulin analogue or premixed insulin, alone or in combination with one or two OAD(s).
  • OADs oral anti-diabetic drugs
  • human NPH insulin or long-acting insulin analogue or premixed insulin alone or in combination with one or two OAD(s).
  • CV death may be defined as death, wherein the cause of death is selected from the group consisting of cardiovascular disease or is unknown. In some embodiments CV death may be defined as death where no clearly documented non-cardiovascular cause exists. CV death may include death resulting from an acute myocardial infarction, sudden cardiac death, death due to heart failure, death due to stroke, death due to cardiovascular procedures, death due to CV haemorrhage, and death due to other CV causes with a specific, known CV cause (e.g., pulmonary embolism or peripheral arterial disease).
  • CV cause e.g., pulmonary embolism or peripheral arterial disease.
  • Non-fatal MI may be defined as myocardial necrosis consistent with myocardial ischemia without death of the subject.
  • MI is diagnosed based on the redefinitions suggested by the ESC (European Society of Cardiology)/ACCF (American College of Cardiology Foundation)/AHA (American Heart Association)/WHF (World Heart Federation) task force, as described in Thygesen K, et al. "Universal Definition of Myocardial Infarction.” J Am Coll Cardiol 2007 Nov 27; 50 (22): 2173-95 .
  • Revascularisation may be defined as restoration of perfusion to a body part or organ that has suffered ischemia, e.g. by unblocking obstructed or disrupted blood vessels or by surgically implanting replacements such as a stent. More specifically, “coronary revascularisation” may be defined as improvement of myocardial blood flow, and “peripheral revascularisation” may be defined as improvement of peripheral arterial blood flow.
  • “Hospitalisation for unstable angina pectoris” may be defined as unscheduled hospitalisation characterised by 1) ischemic discomfort ⁇ 10 minutes in duration occurring at rest, or in an accelerating pattern with frequent episodes associated with progressively decreased exercise capacity; 2) no elevation in cardiac biomarkers and no evidence of acute MI; and 3) at least one selected from the group consisting of: a.
  • New or worsening ST or T wave changes on resting ECG in the absence of confounders, such as LBBB or LVH
  • Transient ST elevation (duration ⁇ 20 minutes)
  • new ST elevation at the J point in two contiguous leads with the cut-points ⁇ 0.1 mV in all leads other than leads V2-V3 where the following cut-points apply: ⁇ 0.2 mV in men ⁇ 40 years ( ⁇ 0.25 mV in men ⁇ 40 years) or ⁇ 0.15 mV in women, and/or ST depression and T-wave changes, and/or New horizontal or down-sloping ST depression ⁇ 0.05 mV in two contiguous leads and/or new T inversion ⁇ 0.3 mV in two contiguous leads with prominent R wave or R/S ratio > 1; b.
  • Definite evidence of inducible myocardial ischemia as demonstrated by: an early positive exercise stress test, defined as ST elevation or ⁇ 2 mm ST depression prior to 5 mets, or stress echocardiography (reversible wall motion abnormality), or myocardial scintigraphy (reversible perfusion defect), or MRI (myocardial perfusion deficit under pharmacologic stress), and believed to be responsible for the myocardial ischemic symptoms/signs; c. Angiographic evidence of new or worse ⁇ 70% lesion and/or thrombus in an epicardial coronary artery that is believed to be responsible for the myocardial ischemic symptoms/signs; and d.
  • PCI coronary revascularization procedure
  • CABG coronary revascularization procedure
  • Non-fatal stroke may be defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of haemorrhage or infarction, e.g., ischemic stroke, or haemorrhagic stroke, without death of the subject.
  • ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of central nervous system tissue(for example, haemorrhage may be a consequence of ischemic stroke, and in this situation, the stroke is an ischemic stroke with haemorrhagic transformation and not a haemorrhagic stroke).
  • haemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal dysfunction caused by intraparenchymal, intraventricular, or subarachnoid haemorrhage.
  • “Hospitalisation for heart failure” may be defined as hospitalisation for at least 24 hours with a primary diagnosis of heart failure; wherein at least one of the following clinical manifestations of heart failure is present: Dyspnoea (dyspnoea with exertion, dyspnoea at rest, orthopnea, paroxysmal nocturnal dyspnoea), decreased exercise tolerance, fatigue, and other symptoms of worsened end-organ perfusion or volume overload; and wherein initiation or intensification of treatment specifically for heart failure including at least one of: a. augmentation in oral diuretic therapy, b. intravenous diuretic, inotrope, or vasodilator therapy, c. mechanical or surgical intervention (including: i.
  • Mechanical circulatory support e.g., intra-aortic balloon pump, ventricular assist device
  • Mechanical fluid removal e.g., ultrafiltration, hemofiltration, dialysis
  • Other symptoms of worsened end-organ perfusion or volume overload may include (i) at least TWO physical examination findings OR (ii) one physical examination finding and at least ONE laboratory criterion), including: a. Physical examination findings considered to be due to heart failure, including new or worsened: i. Peripheral oedema, ii. Increasing abdominal distention or ascites (in the absence of primary hepatic, disease), iii. Pulmonary rales/crackles/crepitations, iv.
  • BNP B-type natriuretic peptide
  • NT-proBNP N-terminal pro-BNP
  • Radiological evidence of pulmonary congestion iii.
  • Non-invasive diagnostic evidence of clinically significant elevated left- or right-sided ventricular filling pressure or low cardiac output for example, echocardiographic criteria could include: E/e' > 15 or D-dominant pulmonary venous inflow pattern, plethoric inferior vena cava with minimal collapse on inspiration, or decreased left ventricular outflow tract (LVOT) minute stroke distance (time velocity integral (TVI))); OR iv. Invasive diagnostic evidence with right heart catheterization showing a pulmonary capillary wedge pressure (pulmonary artery occlusion pressure) ⁇ 18 mmHg, central venous pressure ⁇ 12 mmHg, or a cardiac index ⁇ 2.2 L/min/m 2 .
  • the use of the present invention reduce the occurrence of an event. In some embodiments the use of the present invention reduce the occurrence of an event compared to placebo.
  • the subject to be administered semaglutide according to the present invention may be human, such as an adult human. In some embodiments said subjects are adults.
  • the subject to receive semaglutide administration according to the use of the present invention has type 2 diabetes as well as (i) clinical evidence of cardiovascular disease, and/or (ii) subclinical evidence of cardiovascular disease.
  • cardiovascular diseases may be referred to as concomitant, i.e. one or more cardiovascular diseases are present in the subject at the same time as type 2 diabetes.
  • Chronic evidence of cardiovascular disease may be present when the subject fulfils at least one criterion selected from the group consisting of
  • clinical evidence of cardiovascular disease is prior myocardial infarction. In some embodiments clinical evidence of cardiovascular disease is prior stroke or transient ischaemic attack (TIA). In some embodiments clinical evidence of cardiovascular disease is prior coronary, carotid or peripheral arterial revascularisation. In some embodiments clinical evidence of cardiovascular disease is >50% stenosis on angiography or imaging of coronary, carotid or lower extremity arteries. In some embodiments clinical evidence of cardiovascular disease is history of symptomatic coronary heart disease (e.g. documented by positive exercise stress test or any cardiac imaging or unstable angina with ECG changes). In some embodiments clinical evidence of cardiovascular disease is asymptomatic cardiac ischemia (e.g. documented by positive nuclear imaging test or exercise test or stress echo or any cardiac imaging).
  • TIA transient ischaemic attack
  • clinical evidence of cardiovascular disease is heart failure New York Heart Association (NYHA) class II-III.
  • clinical evidence of cardiovascular disease is chronic renal impairment (e.g., documented (prior to screening) by estimated glomerular filtration rate (eGFR) ⁇ 60 mL/min/1.73m 2 per MDRD).
  • Subject clinical evidence of cardiovascular disease may be present when the subject fulfils at least one criterion selected from the group consisting of
  • subclinical evidence of cardiovascular disease is persistent microalbuminuria (30-299 mg/g) or proteinuria. In some embodiments subclinical evidence of cardiovascular disease is hypertension and left ventricular hypertrophy by ECG or imaging. In some embodiments subclinical evidence of cardiovascular disease is left ventricular systolic or diastolic dysfunction by imaging. In some embodiments subclinical evidence of cardiovascular disease is ankle/brachial index ⁇ 0.9.
  • the term "prior" refers to before initiating administration of semaglutide.
  • characteristics of the subject described herein refers to before initiating administration of semaglutide or at the time of initiating administration of semaglutide.
  • the subject is at least 50 years of age, such as at least 60 years of age. In some embodiments the subject is less than 60 years of age. In some embodiments the subject (i) is at least 50 years of age and has clinical evidence of cardiovascular disease, and/or (ii) is at least 60 years of age and has subclinical evidence of cardiovascular disease.
  • the subject has HbA 1c of at least 7.0%, e.g. prior to receiving semaglutide administration. In some embodiments the subject has HbA 1c of at least 9.0%, e.g. prior to receiving semaglutide administration. In some embodiments the subject has HbA 1c in the range from 7.0% to 15.0%, e.g. prior to receiving semaglutide administration. HbA 1c may be determined according to methods known in the art, for example as a percentage determined according to the method defined by the Diabetes Control and Complications Trial (DCCT), see New Engl J Med 1993;329:977-986 .
  • DCCT Diabetes Control and Complications Trial
  • the subject is, except for semaglutide, anti-diabetic drug naive or treated with one or more oral anti-diabetic drugs (OADs) or treated with human NPH insulin or long-acting insulin analogue or premixed insulin, alone or in combination with one or two OAD(s).
  • OADs oral anti-diabetic drugs
  • the subject may be anti-diabetic drug naive.
  • the subject may be treated with one or more oral anti-diabetic drugs (OADs).
  • the subject may be treated with human NPH insulin or long-acting insulin analogue or premixed insulin, alone or in combination with one or two OAD(s).
  • the OAD may be selected from the group consisting of sulfonylureas, insulin secretagogues, thiazolidinediones, alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, and combinations thereof.
  • the OAD is sulfonylurea (e.g. glimepiride, glipizide, glyburide).
  • the OAD is insulin secretagogues (e.g. biguanides such as metformin or meglitinides such as nateglinide).
  • the OAD is thiazolidinediones (e.g.
  • the OAD is alpha-glucosidase inhibitors (e.g. acarbose, miglitol, voglibose).
  • the OAD is sodium-glucose co-transporter-2 inhibitors (e.g. dapagliflozin, canagliflozin, empagliflozin).
  • the OAD is dipeptidyl peptidase-4 inhibitors (e.g. sitagliptin). In some embodiments the OAD is not a dipeptidyl peptidase-4 inhibitor.
  • the subject has a BMI of no more than 30 kg/m 2 , e.g. prior to receiving semaglutide administration. In some embodiments the subject does not have a BMI of at least 30 kg/m 2 , e.g. prior to receiving semaglutide administration.
  • BMI body mass index
  • BMI weight in kilograms
  • the subject has a BMI in the range of 30-50 kg/m 2 .
  • the subject is male. In some embodiments the subject is not female. In some embodiments the subject is of Asian ethnic origin. In some embodiments the subject is not of ethnic origin other than Asian.
  • NYHA New York Heart Association Functional Classification
  • Table A The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256).
  • the subject has heart failure NYHA class I-III, such as class I, class II or class III. Table A.
  • NYHA class I-IV criteria NYHA Class Functional Capacity of the subject
  • the subject has no heart failure or has heart failure NYHA class I, e.g. prior to receiving semaglutide administration. In some embodiments the subject has heart failure or has heart failure NYHA class I, e.g. prior to receiving semaglutide administration. In some embodiments the subject does not have heart failure NYHA class II or III, e.g. prior to receiving semaglutide administration. In some embodiments the subject does not have heart failure NYHA class II, III or IV, e.g. prior to receiving semaglutide administration.
  • Estimated glomerular filtration rate may be calculated based on serum creatinine concentration followed by either the equation Modification of Diet in Renal Disease (MDRD) or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), both involving variables for age, gender, and ethnic origin of the subject.
  • MDRD Modification of Diet in Renal Disease
  • CKD-EPI Chronic Kidney Disease Epidemiology Collaboration
  • eGFR determined by MDRD may be referred to as eGFR-MDRD.
  • eGFR determined by CKD-EPI may be referred to as eGFR-CKD-EPI.
  • IBW ideal body weight
  • the subject does not have type 1 diabetes.
  • the subject does not receive administration of a GLP-1 receptor agonist (exenatide, liraglutide or other) or pramlintide prior to initiating administration of semaglutide according to the present invention, such as within 100 days or within 104 days prior to this initiation.
  • a GLP-1 receptor agonist exenatide, liraglutide or other
  • pramlintide prior to initiating administration of semaglutide according to the present invention, such as within 100 days or within 104 days prior to this initiation.
  • the subject does not receive administration of a DPP-IV inhibitor prior to initiating administration of semaglutide according to the present invention, such as within 30 days or within 44 days prior to this initiation.
  • the subject does not receive administration of insulin other than basal and pre-mixed insulin (except for short-term use in connection with intercurrent illness) prior to initiating administration of semaglutide according to the present invention, such as within 90 days or within 104 days prior to this initiation.
  • the subject does not have acute decompensation of glycaemic control requiring immediate intensification of treatment to prevent acute complications of diabetes (eg diabetes ketoacidosis) prior to initiating administration of semaglutide according to the present invention, such as within 90 days or 104 days prior to this initiation.
  • acute complications of diabetes eg diabetes ketoacidosis
  • the subject does not have a history of chronic pancreatitis or idiopathic acute pancreatitis prior to initiating administration of semaglutide according to the present invention.
  • the subject does not have acute coronary or cerebrovascular event within 90 days prior to initiating administration of semaglutide according to the present invention.
  • the subject does not have currently planned coronary, carotid or peripheral artery revascularisation prior to initiating administration of semaglutide according to the present invention.
  • the subject does not have heart failure NYHA class IV prior to initiating administration of semaglutide according to the present invention.
  • the subject does not have chronic haemodialysis or chronic peritoneal dialysis prior to initiating administration of semaglutide according to the present invention.
  • End stage liver disease may be defined as the presence of acute, or chronic liver disease and recent history of one or more of the following: ascites, encephalopathy, variceal bleeding, bilirubin ⁇ 2.0 mg/dL, albumin level ⁇ 3.5 g/dL, prothrombin time ⁇ 4 seconds prolonged, international normalised ratio (INR) ⁇ 1.7 or prior liver transplant.
  • the subject has not had a prior solid organ transplant or is not awaiting solid organ transplant prior to initiating administration of semaglutide according to the present invention.
  • the subject does not have a diagnosis of malignant neoplasm in the previous 5 years (except basal cell skin cancer or squamous cell skin cancer) prior to initiating administration of semaglutide according to the present invention.
  • the subject does not have a personal or family history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma prior to initiating administration of semaglutide according to the present invention.
  • the subject does not have a personal history of non-familial medullary thyroid carcinoma prior to initiating administration of semaglutide according to the present invention.
  • the subject does not have calcitonin ⁇ 50 ng/L within 2 weeks prior to initiating administration of semaglutide according to the present invention.
  • the subject does not simultaneously participate in any other clinical trial of an investigational agent, expect for participation in a clinical trial with investigational stent(s).
  • the subject does not receive administration of any investigational medicinal product (IMP) within 45 days prior to initiating administration of semaglutide according to the present invention.
  • IMP investigational medicinal product
  • the subject is not female of childbearing potential who is pregnant, breast-feeding or intends to become pregnant prior to initiating administration of semaglutide according to the present invention.
  • Semaglutide is the GLP-1 receptor agonist N 6.26 - ⁇ 18-[N-(17-carboxy-heptadecanoyl)-L- ⁇ -glutamyl]-10-oxo-3,6,12,15-tetraoxa-9,18-diazaoctadecanoyl ⁇ -[8-(2-amino-2-propanoic acid),34-L-arginine]human glucagon-like peptide 1(7-37), its structure is shown in Chem (I).
  • Semaglutide may also be referred to as N-epsilon26-[2-(2- ⁇ 2-[2-(2- ⁇ 2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy ⁇ ethoxy)acetylamino]ethoxy ⁇ ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37).
  • Semaglutide may be prepared as described in Example 4 of WO2006/097537 .
  • Semaglutide may be administered in the form of a pharmaceutical composition.
  • the pharmaceutical composition may comprise semaglutide in a concentration from 0.1 mg/ml to 100 mg/ml.
  • the pharmaceutical composition comprises 0.01-50 mg, or 0.01-20 mg, or 0.01-10 mg/ml semaglutide.
  • the pharmaceutical composition comprises 0.1-20 mg/ml semaglutide.
  • compositions described herein may further comprise one or more pharmaceutically acceptable excipients, for example selected from the group consisting of buffer system, preservative, tonicity agent, chelating agent, stabilizer and surfactant.
  • the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, such as one or more selected from the group consisting of a buffer, an isotonic agent, and a preservative.
  • the formulation of pharmaceutically active ingredients with various excipients is known in the art, see e.g. Remington: The Science and Practice of Pharmacy (e.g. 19th edition (1995 ), and any later editions).
  • excipient broadly refers to any component other than the active therapeutic ingredient(s), e.g. semaglutide.
  • the excipient may be an inert substance, an inactive substance, and/or a not medicinally active substance.
  • the pharmaceutical composition comprises a phosphate buffer, such as a sodium phosphate buffer, e.g. disodium phosphate.
  • a phosphate buffer such as a sodium phosphate buffer, e.g. disodium phosphate.
  • the pharmaceutical composition comprises an isotonic agent, such as propylene glycol.
  • the pharmaceutical composition comprises a preservative, such as phenol.
  • the pharmaceutical composition may be in the form of a solution or a suspension.
  • the pharmaceutical composition is aqueous composition, such as an aqueous solution or an aqueous suspension.
  • aqueous composition is defined as a composition comprising at least 50 %w/w water.
  • aqueous solution is defined as a solution comprising at least 50 %w/w water
  • aqueous suspension is defined as a suspension comprising at least 50 %w/w water.
  • An aqueous composition may comprise at least 50% w/w water, or at least 60%, 70%, 80%, or even at least 90% w/w of water.
  • the pharmaceutical composition has a pH in the range of 7.0-9.0, such as 7.0-8.5.
  • semaglutide is administered in the form of a pharmaceutical composition comprising about 0.1-20 mg/ml semaglutide, about 2-15 mM phosphate buffer, about 2-25 mg/ml propylene glycol, about 1-18 mg/ml phenol, and has a pH in the range of 7.0-9.0.
  • semaglutide is administered in the form of a pharmaceutical composition comprising about 1.34 mg/ml semaglutide, about 1.42 mg/ml disodium phosphate dihydrate, about 14.0 mg/ml propylene glycol, about 5.5 mg/ml phenol, and has pH of about 7.4.
  • semaglutide is administered in the form of a pharmaceutical composition comprising 1.34 mg/ml semaglutide, 1.42 mg/ml disodium phosphate dihydrate, 14.0 mg/ml propylene glycol, 5.5 mg/ml phenol, and has pH of 7.4.
  • Semaglutide may be administered in a therapeutically effective amount, such as an amount therapeutically effective to treat type 2 diabetes.
  • the therapeutically effective amount of semaglutide can be assessed by a medical doctor.
  • the dosage of semaglutide may be in the range from 0.01 to 10 mg.
  • Semaglutide may be administered once weekly or more frequent, such as once daily. In some embodiments semaglutide is administered at any time in the day. In some embodiments the dosage of semaglutide is in the range from 0.1 to 5.0 mg, such as in the range from 0.1 to 3.0 mg. In some embodiments the daily dosage of semaglutide is selected from the group consisting of 0.5 and 1.0 mg.
  • chronic treatment as used herein with reference to semaglutide means administration in an amount and frequency to provide a therapeutic effect.
  • the term “chronic treatment” as used herein with reference to semaglutide means once weekly administration of 0.1-3.0 mg, such as 0.5 or 1.0 mg, semaglutide.
  • the term “chronic treatment” as used herein with reference to semaglutide means once daily administration of 0.05-0.3 mg, such as 0.05, 0.1, 0.2, or 0.3 mg, semaglutide.
  • semaglutide is administered in an amount in the range of 0.05-2.0 mg per week, such as 0.5 or 1.0 mg per week, optionally by once weekly administration. In some embodiments semaglutide is administered in an amount of at least 0.1 mg per week, such as at least 0.2 mg per week or at least 0.3 mg per week, optionally by once weekly administration. In some embodiments semaglutide is administered in an amount of no more than 1.8 mg per week, such as no more than 1.6 mg per week or no more than 1.4 mg per week, optionally by once weekly administration. In some embodiments semaglutide is administered once weekly in an amount of 0.5 or 1.0 mg. In some embodiments semaglutide is administered in an amount less than 0.7 mg per week, such as in the range of 0.05-0.7 mg per week, optionally by once weekly administration.
  • Semaglutide may be administered via parenteral administration, for example subcutaneous injection. Semaglutide may be administered using a pen-injector, such as a 3 ml disposable pen-injector.
  • chronic treatment may refer to administration of a drug according to a prescribed dosage regimen (for example once weekly administration) for a long period of time (for example at least 2 years or at least 5 years) wherein up to 10%, such as up to 5%, of dosages may be missed; provided that no more than 10 consecutive dosages are missed.
  • ranges herein include their end points.
  • the term “a” means “one or more”.
  • terms presented in singular form also include the plural situation.
  • the term “about” means ⁇ 10% of the value referred to, and includes the value.
  • the subjects were randomised to receive once weekly treatment doses of 0.5 mg semaglutide, 1.0 mg semaglutide, or volume-matched placebo, as an add-on to their standard-of-care treatment, wherein administration started with an initial dose escalation step at 0.25 mg semaglutide once weekly for 4 weeks, and for the 1.0 mg semaglutide group an additional 4 week period at 0.5 mg semaglutide once weekly, or their volume-matched placebo, as shown in Table 1. Additional glucose-lowering medications were allowed to be added to the anti-diabetic regimen to maintain target glycaemic control at the discretion of investigator.
  • Semaglutide was administered in the form of an aqueous solution comprising semaglutide or placebo, both using a 3 ml disposable pen-injector. This pen-injector was identical for the semaglutide and placebo administrations.
  • This aqueous solution contained 1.34 mg/ml semaglutide, 1.42 mg/ml disodium phosphate dihydrate, 14.0 mg/ml propylene glycol, 5.5 mg/ml phenol, at pH 7.40.
  • Semaglutide may be prepared as described in Example 4 of WO2006/097537 .
  • Injections were administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were administered on the same day of the week during the trial. Table 2.
  • Subject inclusion and exclusion criteria all inclusion criteria were fulfilled for eligible subjects; one or more exclusion criteria were fulfilled for subjects to be excluded
  • Definiiton Inclusion Criteria • Men or women with type 2 diabetes. • Age ⁇ 50 years at screening and clinical evidence of cardiovascular disease, OR age ⁇ 60 years at screening and subclinical evidence of cardiovascular disease. • HbA 1c ⁇ 7.0% at screening.
  • OADs oral anti-diabetic drugs
  • Exclusion Criteria • Type 1 diabetes. • Use of a GLP-1 receptor agonist (exenatide, liraglutide or other) or pramlintide within 90 days prior to screening (trial start). • Use of any DPP-IV (dipeptidyl peptidase IV) inhibitor within 30 days prior to screening.
  • End stage liver disease defined as the presence of acute, or chronic liver disease and recent history of one or more of the following: ascites, encephalopathy, variceal bleeding, bilirubin ⁇ 2.0 mg/dL, albumin level ⁇ 3.5 g/dL, prothrombin time ⁇ 4 seconds prolonged, international normalised ratio (INR) ⁇ 1.7 or prior liver transplant.
  • Baseline characteristics of subjects are shown in Table 3.
  • Table 3. Baseline characteristics Semaglutide Placebo Age (year) a 64.7 [50; 89] 64.6 [50; 88] Sex (N, %)
  • White 1384 (84.0) 1352 (82.0) Black or African-American 108 (6.6) 113 (6.9) Asian 121 (7.3) 152 (9.2) Other 35 (2.1) 32 (1.9) Body weight (kg) a 92.4 [40.7; 192] 91.9 [40.7; 217] BMI (kg/m2) a 32.8 [19.3; 77.7] 32.8 [17.6; 61.4] Diabetes duration (years) 14.2 [0.10; 49.9] 13.6 [0.10; 53.9] HbA1c (%) 8.70 [6.60; 17.9] 8.70 [5.90; 15.2] FPG (mmol/L) 10.2 [2.50; 4
  • placebo refers to a formulation identical to the semaglutide formulation except not comprising semaglutide and the placebo was administered in the volume used in the equivalent semaglutide dosage.
  • baseline herein (e.g. used as part of “baseline characteristics” or “baseline cardiovascular risk profile”) may refer to the level of a certain parameter (e.g. level of HbA1c) by the determination made in connection with the medical visit at the time of randomisation of the subject.
  • baseline refers to a parameter before initiating administration of semaglutide, e.g. the history of a certain event in a subject.
  • results of this trial may be presented herein as a number or fraction of subjects experiencing an event.
  • results of this trial may be presented with hazard ratios estimated in a Cox proportional hazard model, which is the standard statistical model used for estimating time to an event.
  • hazard ratio also referred to as "HR” as used herein means the instantaneous risk ratio of experiencing an event when administered semaglutide compared to placebo which are the two treatments in this trial.
  • An upper limit of the 95% confidence interval (CI) for the HR of less than 1.00 means that the estimated treatment ratio between semaglutide and placebo with respect to the event of interest is statistically significant in favour of semaglutide on a 5% significance level.
  • a 5% significance level is the standard level for investigating significance in clinical trials.
  • Fig. 1 shows time to first non-fatal myocardial infarction in a Kaplan-Meier plot.
  • Fig. 2 shows time to first revascularisation.
  • the results in Fig. 1 and Fig. 2 show that semaglutide has particularly good effect in delaying non-fatal myocardial infarction or revascularisation after a certain period of chronic treatment.
  • Time to first MACE selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, revascularization (coronary and peripheral), hospitalisation for unstable angina pectoris (UAP), and hospitalisation for heart failure Hazard ratio [95% CI] Semaglutide Placebo N % N % First MACE ⁇ 0.74 [0.62; 0.89] 199 12.1 264 16.0 Individual components of MACE ⁇ Myocardial infarction, non-fatal 0.74 [0.51; 1.08] 47 2.9 64 3.9 Stroke, non-fatal 0.61 [0.38; 0.99] 27 1.6 44 2.7 Cardiovascular death 0.98 [0.65; 1.48] 44 2.7 46 2.8 Revascularisation 0.65 [0.50; 0.86] 83 5.0 126 7.6 - Coronary revascularisation 0.68 [0.50 ; 0.92] 70 4.2 103 6.2 - Peripheral revascularisation 0.63 [0.34 ; 1.19] 16 1.0 25 1.5 Hospitalisation
  • MACE refers to an event selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, revascularization (coronary and peripheral), hospitalisation for unstable angina pectoris (UAP), and hospitalisation for heart failure. Table 5.
  • MACE is selected from the group consisting of cardiovascular death, non-fatal MI, and non-fatal stroke Factor Hazard ratio [95% CI] Semaglutide Placebo N % N % First MACE ⁇ 0.74 [0.58; 0.95] 108 6.6 146 8.9 Myocardial infarction, non-fatal 46 2.8 64 3.9 Stroke, non-fatal 25 1.5 42 2.5 Cardiovascular death 37 2.2 40 2.4 Sex Female 0.84 [0.54; 1.31] 35 5.5 43 6.5 Male 0.68 [0.50; 0.92] 73 7.2 103 10.4 BMI ⁇ 30 kg/m 2 0.58 [0.39; 0.87] 39 6.6 64 11.0 >30 kg/m 2 0.84 [0.61; 1.16] 69 6.6 82 7.7 Ethnic origin Asian 0.58 [0.25; 1.34] 2 5.7 4 12.5 White 0.76 [0.58; 1.00] 8 6.6 17 11.2 Black or African-American 0.72 [0.23; 2.28] 5
  • MACE refers to an event selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Table 6.
  • MACE is selected from the group consisting of cardiovascular death, non-fatal MI, and non-fatal stroke in each treatment arm of the trial Hazard ratio [95% CI] Semaglutide (N) Placebo (N) First MACE ⁇ 0.5 mg semaglutide 0.77 [0.55; 1.08] 59 77 First MACE ⁇ 1.0 mg semaglutide 0.71 [0.49; 1.02] 49 69 Cox proportional hazard model adjusted for treatment. N: Number of subjects experiencing at least one event. %: Percentage of subjects experiencing at least one event. ⁇ : In this table the term "MACE" refers to an event selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.

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